Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments

Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ + γδ T cells were almos...

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Vydáno v:	Nature immunology Ročník 22; číslo 2; s. 179 - 192
Hlavní autoři:	Lopes, Noella, McIntyre, Claire, Martin, Stefania, Raverdeau, Mathilde, Sumaria, Nital, Kohlgruber, Ayano C., Fiala, Gina J., Agudelo, Leandro Z., Dyck, Lydia, Kane, Harry, Douglas, Aaron, Cunningham, Stephen, Prendeville, Hannah, Loftus, Roisin, Carmody, Colleen, Pierre, Philippe, Kellis, Manolis, Brenner, Michael, Argüello, Rafael J., Silva-Santos, Bruno, Pennington, Daniel J., Lynch, Lydia
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.02.2021 Nature Publishing Group
Témata:	631/250 631/250/1619/554/2509 631/67 692/699 Adaptive immunology Adoptive transfer Animals Antitumor activity Biomedical and Life Sciences Biomedicine Breast Neoplasms - immunology Breast Neoplasms - metabolism Breast Neoplasms - pathology Breast Neoplasms - therapy Cancer Cancer immunotherapy Cell differentiation Cell Line, Tumor Cell Lineage Colonic Neoplasms - immunology Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Colonic Neoplasms - therapy Effector cells Energy Metabolism Female Glucose - metabolism Glycolysis Humans Immune response Immunology Immunotherapy Immunotherapy, Adoptive Infectious Diseases Interferon-gamma - metabolism Interleukin 17 Interleukin-17 - metabolism Life Sciences Lipid Metabolism Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - metabolism Lymphocytes, Tumor-Infiltrating - transplantation Melanoma, Experimental - immunology Melanoma, Experimental - metabolism Melanoma, Experimental - pathology Melanoma, Experimental - therapy Metabolism Mice Mice, Inbred C57BL Mice, Transgenic Microenvironments Mitochondria Mitochondria - metabolism Obesity Obesity - immunology Obesity - metabolism Organ Culture Techniques Oxidative metabolism Phenotype Receptors, Antigen, T-Cell, gamma-delta - metabolism Signal Transduction Supplements T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism T-Lymphocyte Subsets - transplantation Thymus Thymus Gland - immunology Thymus Gland - metabolism Tumor Burden Tumor Microenvironment Tumors γ-Interferon
ISSN:	1529-2908, 1529-2916, 1529-2916
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Shrnutí:	Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ + γδ T cells were almost exclusively dependent on glycolysis, IL-17 + γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17 + γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ + γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy. γδ T cells have potent effector functions through their production of IFN-γ or IL-17. Pennington and colleagues demonstrate that IFN-γ + γδ T and IL-17 + γδ T cells have distinct metabolic requirements that can be independently targeted to elicit specific immune responses.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work.
ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-020-00848-3